Multi‐Enzyme Co‐Expressed Nanomedicine for Anti‐Metastasis Tumor Therapy by Up‐Regulating Cellular Oxidative Stress and Depleting Cholesterol

Abstract Tumor cells movement and migration are inseparable from the integrity of lipid rafts and the formation of lamellipodia, and lipid rafts are also a prerequisite for the formation of lamellipodia. Therefore, destroying the lipid rafts is an effective strategy to inhibit tumor metastasis. Herein, a multi‐enzyme co‐expressed nanomedicine: cholesterol oxidase (CHO) loaded Co─PN₃ single‐atom nanozyme (Co─PN₃ SA/CHO) that can up‐regulate cellular oxidative stress, disrupt the integrity of lipid rafts, and inhibit lamellipodia formation to induce anti‐metastasis tumor therapy, is developed. In this process, Co─PN₃ SA can catalyze oxygen (O₂) and hydrogen peroxide (H₂O₂) to generate reactive oxygen species (ROS) via oxidase‐like and Fenton‐like properties. The doping of P atoms optimizes the adsorption process of the intermediate at the active site and enhances the ROS generation properties of nanomedicine. Meantime, O₂ produced by catalase‐like catalysis can combine with excess cholesterol to generate more H₂O₂ under CHO catalysis, achieving enhanced oxidative damage to tumor cells. Most importantly, cholesterol depletion in tumor cells also disrupts the integrity of lipid rafts and inhibits the formation of lamellipodia, greatly inhibiting the proliferation and metastasis of tumor cells. This strategy by up‐regulating cellular oxidative stress and depleting cellular cholesterol constructs a new idea for anti‐metastasis–oriented cancer therapy strategies.